RT Journal Article
SR Electronic
T1 Aberrant calcium signaling in astrocytes inhibits neuronal excitability in a human Down syndrome stem cell model
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 247585
DO 10.1101/247585
A1 Grace O. Mizuno
A1 Yinxue Wang
A1 Guilai Shi
A1 Yizhi Wang
A1 Junqing Sun
A1 Stelios Papadopoulos
A1 Gerard J. Broussard
A1 Elizabeth K. Unger
A1 Wenbin Deng
A1 Jason Weick
A1 Anita Bhattacharyya
A1 Chao-Yin Chen
A1 Guoqiang Yu
A1 Loren L. Looger
A1 Lin Tian
YR 2018
UL http://biorxiv.org/content/early/2018/01/14/247585.abstract
AB Down syndrome (DS) is a devastating genetic disorder causing severe cognitive impairment. The staggering array of effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We developed an in vitro system to examine the interplay of neurons and astrocytes in a fully recapitulated HSA21 trisomy model differentiated from DS patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we utilized this system to investigate the functional defects of DS astroglia and their effects on neuronal excitability. We found that, compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. DS astrocytes exerted this effect on both DS and healthy neurons. Neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated astrocyte–neuron signaling or genetically by knockdown of inositol triphosphate (IP3) receptors or S100β, a calcium binding protein coded on HSA21. Our results suggest a novel mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability. Furthermore, our study establishes an all-optical neurophysiological platform for studying human neuron-astrocyte interactions associated with neurological disorders.Significant statement Down syndrome (DS) is the most common genetic disorder caused by trisomy of chromosome 21 (HSA21). Problems with cognitive impairment, have not been properly addressed due to the inability to fully recapitulate HSA21, which is further confounded by the snapshot views of morphological changes of brain cells in isolation obtained from current studies. The brain develops neural networks consisting of neurons and glial cells that work together. To understand how DS affects the neural networks, we used DS patient-derived stem cells and calcium imaging to investigate functional defects of DS astrocytes and their effects on neuronal excitability. Our study has significant implication in understanding functional defects during brain development underlying DS.